OVERALL ABSTRACT The application describes the creation of a new center that will focus on the development of Positron Emission Tomography (PET) ligands for imaging two proteinopathies: 1) alpha synuclein (Asyn) for imaging the synucleinopathies Parkinson's disease and multiple system atrophy; and, 2) 4R tau for imaging the 4R tauopathies frontotemporal degeneration and progressive supranuclear palsy. The name of the proposed center is the Center without Walls for Imaging Proteinopathies with PET (CW2IP2), and represents a multi-institutional collaborative effort between the University of Pennsylvania, Washington University-St. Louis, University of Pittsburgh, University of California-San Francisco, Yale University, and the contract research organization, MedChem Imaging. The organization of this Center without Walls is highly innovative and unique for a variety of reasons: 1) it engages faculty members at the University of Pennsylvania having an international reputation in the fields of neurobiology (V. Lee, K. Luk), neuropathology (J. Trojanowski), and structural biology (E.J. Petersson; V. Moiseenkova-Bell) of the proteinopathies into the field of PET radiotracer development for imaging aggregated Asyn and 4R tau; 2) it involves the collaboration of PET radiochemists at Penn (RH Mach), Pitt (C. Mathis), Wash U (Z. Tu) and MedChem Imaging (N. Vasdev) who are experts in the field of CNS radiotracer development; and 3) it involves the multi-site collaboration of clinical investigators who are experts in the use of PET to study CNS disorders (J Perlmutter (Wash U), R. Carson (Yale), G. Rabinovici (UCSF), A. Siderowf (Penn)). This multi-institutional collaboration not only meets the criteria described in the RFA for the Creation of a Center without Walls, but the participation of individuals having such diverse scientific backgrounds will be essential for successfully accomplishing the scientific objectives of this RFA. The PI of the Center is Robert H. Mach, the Britton Chance Professor of Radiology at Penn. The center consists of an Administrative Core and two research cores: Medicinal Chemistry and Radiochemistry and the Clinical Core. The cores have been organized such that there is an overall Core Director or Co-Director, and a site Director at each of the sites participating in the Core activities. There are two research projects in this U19 Center, each focused on studies aimed at validation probes developed by the Medicinal Chemistry and Radiochemistry Core for a proteinopathy (Project 1/Asyn and Project 2/4R tau). This U19 Center will also implement a broad-based Data and Resource Sharing Plan that will be of benefit to clinical investigators in the US who are conducting research relevant to the scientific mission of the NINDS and NIA. We anticipate that the Center without Walls for Imaging Proteinopathies with PET (CW2IP2) will lead to a significant expansion of NINDS- and NIA-based translational research at the national level, and will advance our knowledge on the role of Asyn and 4R tau in neurodegeneration.